Chapter 15

Genetic Polymorphisms of Alcohol

Dehydrogense-1B and Aldehyde
Dehydrogenase-2, Alcohol Flushing,
Mean Corpuscular Volume, and Aerodigestive
Tract Neoplasia in Japanese Drinkers

Akira Yokoyama, Takeshi Mizukami, and Tetsuji Yokoyama

Abstract Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) and

aldehyde dehydrogenase-2 (ALDH2) modulate exposure levels to ethanol/acetalde-
hyde. Endoscopic screening of 6,014 Japanese alcoholics yielded high detection
rates of esophageal squamous cell carcinoma (SCC; 4.1 %) and head and neck SCC
(1.0 %). The risks of upper aerodigestive tract SCC/dysplasia, especially of multiple
SCC/dysplasia, were increased in a multiplicative fashion by the presence of a com-
bination of slow-metabolizing ADH1B*1/*1 and inactive heterozygous ALDH2*1/*2
because of prolonged exposure to higher concentrations of ethanol/acetaldehyde.
A questionnaire asking about current and past facial flushing after drinking a glass
(≈ 180 mL) of beer is a reliable tool for detecting the presence of inactive ALDH2.
We invented a health-risk appraisal (HRA) model including the flushing question-
naire and drinking, smoking, and dietary habits. Esophageal SCC was detected at a
high rate by endoscopic mass-screening in high HRA score persons. A total of
5.0 % of 4,879 alcoholics had a history of (4.0 %) or newly diagnosed (1.0 %) gas-
tric cancer. Their high frequency of a history of gastric cancer is partly explained by
gastrectomy being a risk factor for alcoholism because of altered ethanol metabo-
lism, e.g., by blood ethanol level overshooting. The combination of H. pylori-
associated atrophic gastritis and ALDH2*1/*2 showed the greatest risk of gastric
cancer in alcoholics. High detection rates of advanced colorectal adenoma/carci-
noma were found in alcoholics, 15.7 % of 744 immunochemical fecal occult blood
test (IFOBT)-negative alcoholics and 31.5 % of the 393 IFOBT-positive alcoholics.

A. Yokoyama, M.D. (*) • T. Mizukami, M.D.

National Hospital Organization Kurihama Medical and Addiction Center,
5-3-1 Nobi, Yokosuka, Kanagawa 239-0841, Japan
e-mail: [email protected]
T. Yokoyama, M.D.
Department of Health Promotion, National Institute of Public Health, Saitama, Japan

© Springer International Publishing Switzerland 2015 265

V. Vasiliou et al. (eds.), Biological Basis of Alcohol-Induced Cancer,
Advances in Experimental Medicine and Biology 815,
DOI 10.1007/978-3-319-09614-8_15
266 A. Yokoyama et al.

Macrocytosis with an MCV ≥ 106 fl increased the risk of neoplasia in the entire
aerodigestive tract of alcoholics, suggesting that poor nutrition as well as ethanol/
acetaldehyde exposure plays an important role in neoplasia.

Keywords Acetaldehyde • Alcohol dehydrogenase • Alcoholic • Aldehyde dehy-

drogenase • Colorectal neoplasia • Esophageal cancer • Head and neck cancer •
Mean corpuscular volume • Stomach cancer

15.1 Endoscopy and Esophageal Iodine Staining

of Screening Japanese Alcoholic Men for Upper
Aerodigestive Tract Neoplasia

Alcohol consumption, tobacco smoking, inadequate intake of fruits and vegetables,

and low body mass index (BMI) are risk factors for squamous cell carcinoma (SCC)
of the upper aerodigestive tract (UADT, i.e., the oral cavity, pharynx, larynx, and
esophagus), and many alcoholic patients have all of these risk factors. We intro-
duced an endoscopic screening program at Kurihama Medical and Addiction Center
in 1993 [1], and by 2010 initial screening of 6,014 Japanese alcoholic men by
endoscopy combined with head and neck inspection and esophageal iodine staining
had detected esophageal SCC in 243 (4.0 %) of them and head and neck SCC in 65
(1.1 %) of them. Barrett adenocarcinoma was detected in only two patients.
Technical improvements in endoscopes and a growing understanding of the endo-
scopic findings of early SCC in the UADT [2, 3] have enabled very early detection
of SCC in the UADT. Treatment of early SCC in UADT by endoscopic or endoscope-
guided mucosectomy has become a widespread practice in Japan and succeeded in
improving the outcome of this high-mortality cancer [3, 4].

15.2 ALDH2 Genotype and Alcohol Metabolism

Genetic polymorphism of aldehyde dehydrogenase-2 (ALDH2, rs671) modulates

exposure levels to acetaldehyde after drinking (Fig. 15.1). A mutant ALDH2*2 allele
encoding an inactive subunit of ALDH2 was carried by Han Chinese as they spread
throughout East Asia [5]. About 40 % of Japanese, 7 % being homozygotes and 35 %
heterozygotes [6], have the inactive ALDH2*2 allele which acts in a dominant man-
ner. After drinking a small amount of alcohol, people with inactive ALDH2 tend to
experience a flushing response that includes facial flushing, palpitations, nausea, and
drowsiness [7]. People with inactive ALDH2 [8] or with inactive-ALDH2-associated
facial flushing [9] tend to experience a hangover in the morning after drinking a
smaller amount of alcohol than people without either of them. Thus presence of inac-
tive ALDH2 in some East Asians tends to prevent them from drinking heavily [6].
Because of their very intense flushing responses ALDH2*2/*2 homozygotes are
15 Genetic Polymorphisms of Alcohol Dehydrogense-1B… 267

Ethanol Acetaldehyde Acetate

slow-metabolizing inactive heterozygous

ADH1B*1/*1 ALDH2*1/*2

Alcohol flushing , Alcohol flushing

even in ALDH2*1/*2 heterozygotes Hangover susceptibility
Alcoholism susceptibility , Alcoholism susceptibility
especially in the younger generation The protective effect has been
Alcoholics smell of alcohol in the morning weakening during the past 30 yrs.
after heavy drinking Liver disease susceptibility
Liver disease susceptibility in alcoholics Increased accumulation
Weight gain by alcoholics because of
efficient utilization of ethanol energy of acetaldehyde

Prolonged exposure to Neoplasia in the upper

ethanol/acetaldehyde aerodigestive tract

Fig. 15.1 Phenotypes of the alcohol dehydrogenase-1B*1/*1 (ADH1B*1/*1) and aldehyde dehy-
drogenase-2*1/*2 (ALDH2*1/*2) genotypes and their relationships to ethanol and acetaldehyde
exposure and accumulation

usually nondrinkers or occasional drinkers. However, the inhibitory effect of being

heterozygous for inactive ALDH2 on heavy drinking is influenced by sociocultural
factors. The proportion of Japanese alcoholics with the ALDH2*1/*2 genotype
increased dramatically from 2.5 % in 1979, to 8.0 % in 1986, and to 13.0 % in 1992
[10], and the proportion continued to increase from 13.0 % in 1996–2000, to 14.0 %
in 2001–2005, and to 15.4 % in 2006–2010 [11].

15.3 ALDH2 Genotype and Squamous Cell Neoplasia

in the UADT

In 1996, we first reported that being heterozygous for inactive ALDH2 is a strong
risk factor for esophageal cancer in daily drinkers and alcoholics [12]. Since then,
epidemiological studies have almost consistently demonstrated a strong association
between the ALDH2*1/*2 genotype and the risk of UADT cancer in East-Asian
drinkers [13]. A meta-analysis of Asian case–control studies of esophageal cancer
showed that the ALDH2*1/*2-associated odds ratio (95 % confidence interval)
[OR (95 % CI)] for esophageal cancer was 3.12 (1.95–5.02) in moderate drinkers,
5.64 (1.57–20.25) in ex-drinkers, and 7.12 (4.67–10.86) in heavy drinkers [14].
The ALDH2*1/*2 genotype has been found to be a very strong risk factor for esoph-
ageal cancer among Taiwan Chinese and Japanese drinkers (OR = 4.74–6.21 in
moderate drinkers and 9.21–9.75 in heavy drinkers), but the OR associated with the
ALDH2*1/*2 genotype in the high incidence regions of esophageal cancer of
Mainland China was not so high (OR = 1.98 in moderate drinkers and 1.31 in heavy
268 A. Yokoyama et al.

drinkers). The meta-analysis confirmed that being homozygous for the inactive
allele, i.e., having the ALDH2*2/*2 genotype greatly increased the risk of esopha-
geal cancer in drinkers, and that the heterozygous genotype, i.e., ALDH2*1/*2
increased the risk of esophageal cancer in a similar manner in both men and women.
A meta-analysis of 6 Japanese case–control studies showed that the ALDH2*1/*2-
associated risk for head and neck cancer was also greater in heavy drinkers [OR
(95 % CI) = 3.57 (1.21–2.77)] than in moderate drinkers [OR (95 % CI) = 1.68
(1.22–2.27)] [15].
The United States National Cancer Institute’s SEER Program reported synchro-
nous multiple cancers and metachronous multiple cancers in only 2 % and 3 %,
respectively, of esophageal cancer patients during the 1973–2003 period [16]. The
prevalence of multiple organ cancers among esophageal cancer patients treated at
the National Cancer Center of Japan increased at an alarming rate between 1969 and
1996 from 6.3 % in 1969–1980, to 22.2 % in 1981–1991, and to 39.0 % in 1992–
1996 [17], and the most frequent sites of the other cancers were the head and neck
and stomach. The increased proportion of multiple cancers in Japanese esophageal
cancer patients may partly explained by a dramatic increase in the proportion of
ALDH2*1/*2 heterozygotes among Japanese heavy drinkers during the same period
[10]. The ALDH2*1/*2 genotype has consistently been demonstrated to be a strong
determinant of the risk of synchronous and metachronous SCC of the UADT in
Japanese drinkers [13].
The ORs (95 % CI) associated with the ALDH2*1/*2 genotype in Japanese alco-
holics has been found to increase for the very early stages of the esophageal neoplasia,
from 2.88 (1.81–4.57) for low-grade intraepithelial neoplasia, to 5.14 (2.87–9.19)
for high-grade intraepithelial neoplasia, and to 4.07 (1.97–8.40) for invasive SCC
[18]. The presence of multiple esophageal iodine-unstained lesions or a large esoph-
ageal dysplasia has been found to be a strong predictor of the development of mul-
tiple cancers in the UADT in Japanese [13], and to be associated with the
ALDH2*1/*2 genotype [18], p53 alteration [19], and telomere shortening in the
esophagus [20] in Japanese alcoholics. Thus, acetaldehyde, which is an established
human carcinogen, plays a critical role in the multicentric development of neoplasia
throughout the UADT.

15.4 The Simple Flushing Questionnaire

The discovery of ALDH2-associated cancer susceptibility emphasizes the impor-

tance of developing screening tests for inactive ALDH2 based on alcohol flushing.
We devised a flushing questionnaire to identify person with inactive ALDH2
(Fig. 15.2) [21, 22]. The simple flushing questionnaire consists of two questions: (A)
Do you have a tendency to flush in the face immediately after drinking a glass
(≈180 mL) of beer? (B) Did you have a tendency to flush in the face immediately
after drinking a glass of beer during the first to second year after you started drinking?
The results are used to classify the subjects as a current flusher, former flusher, or
15 Genetic Polymorphisms of Alcohol Dehydrogense-1B… 269

Simple Flushing Questionnaire

to identify inactive ALDH2
(A) Do you have tendency to flush in the face
immediately after drinking a glass of beer?
(B) Did you have tendency to flush in the face
immediately after drinking a glass of beer
during the first to second year after you
started drinking?
Yes, No, or Unknown

Current flusher: (A) = Yes.

inactive ALDH2
Former flusher: (A)≠Yes, but (B) = Yes.
Never flusher: Others. active ALDH2

Sensitivity: 90%, specificity: 88%

for identification of persons with inactive ALDH2.

Fig. 15.2 The simple flushing questionnaire to identify persons with inactive ALDH2. Sensitivity
and specificity are both approximately 90 % in Japanese 40 years of age and over, regardless of
gender

never flusher. When current flushers or former flushers were assumed to have inactive
ALDH2, the simple flushing questionnaire had 90 % sensitivity and 88 % specificity
when evaluated in 610 Japanese men 40 years of age or older [22] and 88 % sensitiv-
ity and 92 % specificity when evaluated in 381 Japanese women 40 years of age or
older [23]. The individuals’ risks of UADT cancer estimated on the basis of the replies
to the flushing questionnaire were slightly lower than but essentially comparable to
their risks estimated on the basis of ALDH2 genotyping [21–23].

15.5 Mass-Screening for SCC of the UADT by Means

of Health-Risk Appraisal Models

Based on the results of a case–control study [24], we devised health-risk appraisal

(HRA) models for esophageal cancer that include ALDH2 genotype or alcohol
flushing [25]. The total risk score is calculated by adding the scores A–E (Fig. 15.3).
If a person’s risk score is 11 or more according to the HRA-Flushing model, that
person’s risk of esophageal cancer is in the top 10 % of the study population.
A cross-validation study predicted that approximately 60 % of the esophageal and
hypopharyngeal SCCs in the entire population could be detected by examining only
people whose risk scores were in the top 10 % in the HRA models. Follow-up
endoscopy with esophageal iodine staining (median follow-up period: 5.0 years)
270 A. Yokoyama et al.

Factors Risk score (select one choice each for A-E)

Facial flushing and drinking (1 unit =22 g of ethanol)

Any flushing
Never/rare drinker (<1 unit/week) 0
Never flushing
Total risk score = A + B + C + D + E
Light drinker (1-8.9 units/week) 1
Moderate drinker (9-17.9 units/week) 5
Heavy drinker (18+ units/week) 6
Ex-drinker 7
Current/former flushing
Light drinker (1-8.9 units/week) 4 High -risk scores
Moderate drinker (9-17.9 units/week) 9 Endoscopic screening
Heavy drinker (18+ units/week) 10 A is recommended
Ex-drinker 8
Drink strong alcoholic beverages frequently
Age 50 -69 years 9 or more
Yes 3
B Age ≥ 70 years 8 or more
No 0
Smoked 30 pack-years or more
Yes 2
No
C
0
Eat green -yellow vegetables almost every day
Yes 0
No
D
1
Eat fruit almost every day
Yes 0 E
No 1

Fig. 15.3 Health-risk appraisal model for esophageal cancer combined with the simple flushing
questionnaire. The questionnaire enables makes it possible for people to easily determine their risk
of esophageal cancer, and public awareness campaigns that use the questionnaire will help per-
suade high-risk persons to undergo endoscopic screening or enable them to change their lifestyle
to prevent esophageal cancer

was performed on 404 cancer-free controls and resulted in the diagnosis of six
esophageal SCCs and two pharyngeal SCCs [26]. The risk scores of six of these
eight cancer patients at baseline were in the top 10 % according to the HRA-Flushing
model. The cancer detection rate per 100 person–years in the top 10 % risk group of
the cancer-free controls was 2.3 for esophageal cancer and 3.5 for esophageal or
pharyngeal cancer. We applied this HRA-Flushing questionnaire to endoscopic
mass-screening programs of 2,221 Japanese men during 2008 and 2009 at five can-
cer screening facilities, and esophageal cancer was diagnosed in 19 persons as a
result [27]. The HRA-Flushing score of 5 % of the examinees was 11 or greater, and
esophageal cancer was detected in 4.3 % of them, as opposed to in 0.7 % of the
other examinees. A receiver operating characteristic curve analysis showed that
when we used an cutoff point of an HRA score of ≥9 in the 50–69 age group and of
≥8 in the 70–89 age group to select individuals with a high risk for esophageal can-
cer, the sensitivity and false-positive rate was 52.6 % and 15.2 %, respectively, and
cancer was detected in 2.91 % of the examinees in the high-risk group, as opposed
to 0.48 % in the other group. Although the cutoff values for high-risk groups should
15 Genetic Polymorphisms of Alcohol Dehydrogense-1B… 271

be changed to achieve better performance of the HRA model according to the

population targeted, these figures encouraged using our questionnaire to screen
larger populations of Japanese men.
Our simple questionnaire makes it possible for many people to identify their risk
of UADT cancer very easily, and use of the questionnaire in public awareness cam-
paigns will help persuade high-risk persons to undergo endoscopic screening or
enable them to change their lifestyle to prevent UADT cancer. Our HRA model that
includes ALDH2 genotype yielded a slightly better positive predictive value [25]
and a slightly higher cancer detection rate [26] than the HRA-Flushing model.
Genotyping ALDH2 would entail an initial cost, but genotyping needs to be per-
formed only once in a lifetime, the data are always available, and the unit cost would
be greatly discounted if a huge number of samples are analyzed.

15.6 ADH1B Genotype, Alcohol Metabolism,

and SCC of the UADT

Alcohol dehydrogenase-1B (ADH1B, previously called ADH2) also has a

functional genetic polymorphism (rs1229984; Fig. 15.1). The ADH1B*1/*1 geno-
type, which results in expression of slow-metabolizing ADH1B, is prevalent in
Caucasians (present in approximately 90 %), but present in only a small fraction of
East Asians (e.g., 7 % of Japanese) [6]. The presence of slow-metabolizing ADH1B
is a stronger risk factor for alcoholism and SCC of the UADT in East Asians than
the presence of the fast-metabolizing ADH1B because of having the ADH1B*2
allele. Approximately 30 % of Japanese alcoholics have the slow-metabolizing
ADH1B, and the slow-metabolizing ADH1B has been found to be more frequent in
the younger generations of Japanese alcoholics, probably because the ADH1B*1/*1
genotype accelerates the progression of alcohol dependence [11].
Alcohol challenge tests have failed to demonstrate any associations between
ADH1B genotype and the blood ethanol or acetaldehyde concentrations after inges-
tion of small to moderate doses of ethanol [13]. However, the slow-metabolizing
ADH1B has an approximately 40 times lower Vmax in vitro than the fast-
metabolizing ADH1B [28], and an experiment in which a clamping technique and
intravenous alcohol infusion were used showed a modestly but significantly lower
ethanol elimination rate (11–18 %) among Jews with the slow-metabolizing ADH1B
than with the fast-metabolizing ADH1B [29]. At the time of their first visit to our
Addiction Center, we evaluated associations between ADH1B and ALDH2 geno-
types and the blood ethanol levels of 805 Japanese alcoholic men in the morning
after drinking within the previous 34 h [30]. The results showed no significant
differences in age-adjusted usual alcohol consumption according to ADH1B or
ALDH2 genotypes. Higher blood ethanol levels persisted for longer periods in the
group with the slow-metabolizing ADH1B who were ADH1B*1/*1 carriers (n = 246)
than in the group with the fast-metabolizing ADH1B who were ADH1B*2 carri-
ers (n = 559), and blood ethanol levels ≥0.3 mg/mL (criterion for drunk driving
272 A. Yokoyama et al.

according to Japanese law) after a 12.1–18-h interval since the last drink were
observed in a significantly higher proportion of the ADH1B*1/*1 carriers than of
the ADH1B*2 carriers (40 % vs. 14–17 %, p < 0.0001). Multivariate analyses
showed that the ethanol levels were 0.500 mg/mL higher in the group with the
ADH1B*1*1 genotype, and the OR (95 % CI) for an ethanol level ≥0.3 mg/mL in
the presence of the ADH1B*1/*1 genotype was 3.44 (2.34–5.04). There were no
significant differences in blood ethanol levels according to ALDH2 genotype.
We evaluated associations between ADH1B and ALDH2 genotypes and the body
weight and BMI of 1,301 Japanese alcoholic men on the day of their first visit [31].
There were no significant differences in usual caloric intake in the form of alcoholic
beverages according to ADH1B genotype in any of the age brackets, but the pres-
ence of the slow-metabolizing ADH1B was more strongly associated with weight
gain in all age brackets. This result links the slower ethanol elimination by the
ADH1B*1*/*1 alcoholics with their more efficient utilization of ethanol as an energy
source. No effects of ALDH2 genotype on body weight or BMI were observed.
In a study in which we simultaneously measured the blood and salivary ethanol
and acetaldehyde levels of Japanese alcoholics in the morning on the day of their
first visit [32, 33], we found that ethanol and acetaldehyde remained in the blood
and saliva for much longer periods and at much higher levels in the group with the
slow-metabolizing ADH1B than in the group with the fast-metabolizing ADH1B,
even after adjusting for age, body weight, the amount of alcohol consumed, and
interval since the previous drink. Chronic heavy drinking by alcoholics may amplify
the modest effect of ADH1B*1/*1 on ethanol metabolism and lead to clear prolon-
gation of the presence of ethanol in the body, including in the UADT. The blood and
salivary ethanol levels of the subjects were similar, but the acetaldehyde levels in
their saliva were much higher than in their blood because of acetaldehyde produc-
tion by oral microorganisms. [32, 33]
ADH1B genotype markedly affects alcohol flushing [22, 34]. Alcohol flushing in
fast-metabolizing ADH1B carriers is triggered by a rapid initial rise in the blood
acetaldehyde concentration, whereas the slow initial rise in the blood acetaldehyde
in slow-metabolizing ADH1B carriers may weaken the alcohol flushing [22, 34].
The results of our flushing questionnaire showed that despite the presence of inac-
tive ALDH2 in heterozygotes, 25 % of the slow-metabolizing ADH1B carriers were
never flushers and 38 % were former flushers, and thus there was a clear association
between alcohol consumption by inactive ALDH2 heterozygotes and their facial
flushing categories [22].
The above findings provide clues as to why slow-metabolizing ADH1B increases
the risk of both alcoholism and UADT cancer. First, slow-metabolizing ADH1B
diminishes the intensity of facial flushing, thereby accounting for the greater
susceptibility to heavy drinking. Second, chronic heavy drinking amplifies the mod-
est effect of slow-metabolizing ADH1B on ethanol elimination, which leads to
much longer exposure to ethanol and, in turn, results in increasing the risk of devel-
oping alcoholism. When ethanol lingers in the body, the UADT is exposed to high
levels of acetaldehyde as a result of acetaldehyde production in saliva, and that
creates a condition that increases the risk of UADT cancer.
15 Genetic Polymorphisms of Alcohol Dehydrogense-1B… 273

15.7 The ADH1B*1/*1 and ALDH2*1/*2 Genotype

Combination and SCC in the UADT

The risk of SCC of the head and neck and esophagus of Japanese and Taiwanese
drinkers has been found to be extremely increased in a multiplicative fashion by the
combination of slow-metabolizing ADH1B in the ADH1B*1/*1 genotype and inac-
tive ALDH2 in the ALDH2*1/*2 genotype (OR = 22–122 for esophageal SCC) [13,
18, 24, 35–37]. In Japanese alcoholics, the OR (95 % CI) with the ADH1B*1/*1 and
ALDH2*1/*2 genotype combination has been found to increase for the very early
stages of the esophageal neoplasia, from 4.53 (2.17–9.47) for low-grade intraepithe-
lial neoplasia, to 10.4 (4.34–24.7) for high-grade intraepithelial neoplasia, and 21.7
(7.96–59.3) for invasive SCC [18]. When the two genotypes were combined with
other risk factors, based on the multivariate OR for each risk factor the ORs (95 %
CI) of Japanese for esophageal SCC increased enormously, by 248 times when
combined with consumption of 198–395 g ethanol/week and by 414 times when
combined with consumption of ≥396 g ethanol/week [24], in Taiwanese by 382
(47–3,085) times when combined with consumption of >30 g ethanol/day [35], and
in Japanese by 189 (95–377) times when combined with both consumption of
>96.5 g ethanol/week and smoking [36] and by 357 (105–1,210) times when com-
bined with both drinking and smoking [37].

15.8 ADH1B and ALDH2 Genotype and Liver Disease

in Japanese Alcoholic Men

Contrary to results of investigations of the relationships between the ADH1B and

ALDH2 genotypes and susceptibility to UADT cancer, a cross-sectional survey of 1,902
Japanese alcoholic men showed that liver cirrhosis was associated with the presence of
the ADH1B*2 allele and ALDH2*1/*1 genotype [38]. When non-cirrhotic patients with
no or only mild liver fibrosis as controls, the results showed that the OR (95 % CI) of
the ADH1B*2 allele increased according to the severity of their liver disease, from 1.67
(1.32–2.11) in the non-cirrhotic group with liver fibrosis, to 1.81 (1.24–2.63) in the
Child-Pugh class A cirrhosis group, 2.97 (1.79–4.93) in the Child-Pugh class B cirrho-
sis group, and 4.32 (1.48–12.6) in the Child-Pugh class C cirrhosis group. Since age-
adjusted daily alcohol consumption did not differ according to ADH1B/ALDH2
genotypes in the alcoholics, their ADH1B/ALDH2-associated increase in risk of liver
disease cannot be explained by the levels of ethanol and acetaldehyde exposure.

15.9 Gastric Cancer in Japanese Alcoholic Men

The lifetime drinking profiles of Japanese alcoholic men have shown that gastrec-
tomy increases susceptibility to alcoholism [39]. Gastrectomy results in swift pas-
sage of ethanol from the small intestine into the systemic circulation. Because of
274 A. Yokoyama et al.

this dynamic change in ethanol delivery, overshoot of blood ethanol levels and
subsequent high ethanol exposure have been observed after gastrectomy [40], and
they lead to rapid development of alcohol dependence. A large survey of 4,879
Japanese alcoholic men demonstrated that a high proportion of them had a history
of gastrectomy, although the proportion decreased from 13.3 to 7.8 % during the
1996–2010 period [11]. Many alcoholic men with a history of gastrectomy had
changed their drinking pattern after the gastrectomy and had became alcoholics
after a shorter period of heavy drinking and after a lower cumulative alcohol intake
than alcoholics with no history of gastrectomy [39]. There were more frequent
blackouts in the gastrectomy group, and that may have reflected the sharper rise in
their blood ethanol level. Since a history of gastrectomy increases the risk of alcohol
dependence, this acquired risk factor increases susceptibility to alcohol dependence
in the absence of the alcoholism-susceptibility genotype ADH1B*1/*1, and that
explains the lower frequency of ADH1B*1/*1 that was found in a gastrectomy
group of Japanese alcoholic men than in a non-gastrectomy group [11].
The prevalence of gastric cancer is extremely high among Japanese alcoholic
men. A study of 4,879 Japanese male alcoholic patients revealed that 187 had a his-
tory of gastrectomy for gastric cancer and ten had a history of mucosectomy for
gastric cancer, and 47 were diagnosed with gastric cancer during the initial endo-
scopic screening [11]. A total of 244 (5.0 %) of the patients had a history of gastric
cancer or were newly diagnosed with gastric cancer.
Inactive ALDH2, macrocytosis, and simultaneous presence of UADT cancer as
well as H. pylori-associated atrophic gastritis have been found to be associated with
the risk of gastric cancer detected by endoscopic screening of Japanese alcoholic
men [41]. This finding partly explains why gastric, esophageal, and head and neck
cancers are often concurrent in Japanese alcoholic men. However, the frequency of
the ALDH2*1/*2 genotype in alcoholics with a history of gastrectomy for gastric
cancer was found to be as low as in alcoholics without a history of gastrectomy [11].
These findings suggest different causal associations between alcoholism and each
group of gastric cancer.
The risk of metachronous gastric cancer is high in Japanese with esophageal
SCC, especially among alcoholic men, suggesting a common cause of both cancers.
Endoscopic follow-up (median, 47 months) after the initial diagnosis of esophageal
SCC was performed in 99 Japanese alcoholic men [42]. A serum pepsinogen test
showed a higher seroprevalence of severe chronic atrophic gastritis among the
esophageal SCC cases than among age-matched alcoholic controls, whereas their
H. pylori status was similar. The accelerated progression of severe chronic atrophic
gastritis observed in Japanese alcoholic men with esophageal SCC suggests the exis-
tence of a common mechanism by which both esophageal SCC and H. pylori-related
severe chronic atrophic gastritis develop in the alcoholics. Metachronous gastric
adenocarcinoma was diagnosed in 11 of the 99 gastric cancer-free patients in the
same study, and the cumulative rate of metachronous gastric cancer within 5 years
was estimated to be 15 %. The hazard ratio [HR (95 % CI)] of metachronous gastric
cancer was 7.87 (1.43–43.46) in the group with severe chronic atrophic gastritis in
comparison with the group without chronic atrophic gastritis. Inactive heterozygous
15 Genetic Polymorphisms of Alcohol Dehydrogense-1B… 275

ALDH2 was not associated with an increased risk of metachronous gastric cancer.
Accelerated development of severe chronic atrophic gastritis at least partially
explained the very high frequency of development of metachronous gastric cancer in
this population of Japanese men with an initial diagnosis of SCC of the esophagus.

15.10 Colonoscopic Screening of Japanese Alcoholic

Men for Colorectal Neoplasia

The results of colonoscopic screening of Japanese alcoholic men for colorectal neo-
plasia yielded an extremely high rate of advanced colorectal neoplasia: 15.7 % in
the group of 744 subjects with a negative immunochemical fecal occult blood test
(IFOBT) and 31.6 % in the group of 393 subjects with a positive IFOBT [43].
Advanced colorectal neoplasia has been reported to have been detected in 2.6 % of
an IFOBT-negative group and 16.0 % of an IFOBT-positive group in the Japanese
general population [44]. Advanced colorectal neoplasia includes adenomas
≥10 mm, villous and tubulovillous adenomas, high-grade dysplasia, carcinoma-in-
situ, and invasive cancers. Thus, screening alcoholic men by the IFOBT alone is
inadequate, and colonoscopy should be recommended to the patients. There were
no significant associations between ALDH2 genotypes and the risk of advanced
colorectal neoplasia [43].

15.11 Association Between a High Mean Corpuscular

Volume and Increased Risk of Aerodigestive Tract
Neoplasia in Japanese Alcoholic Men

Epidemiological evidence indicates that the red cell mean corpuscular volume
(MCV) of inactive ALDH2 carriers is increased by exposure to acetaldehyde [45–
51]. Alcoholism, severe acetaldehyde exposure because of the presence of inactive
ALDH2, smoking, low BMI, and folate deficiency are associated with both increased
MCV and increased risk of aerodigestive tract cancer. The simultaneous presence of
a high MCV of 106 or more, ALDH2*1/*2 genotype, and ADH1B*1/*1 genotype in
Japanese alcoholic men synergistically increase their risk of esophageal SCC [OR
(95 % CI) = 320 (27–>1,000)] [47]. An endoscopic follow-up study of cancer-free
Japanese alcoholics revealed that cancer of the UADT developed much more fre-
quently among alcoholics with a high MCV of 106 or more [HR (95 % CI) = 2.52
(1.22–5.22)] [51]. An MCV of 106 or more in Japanese alcoholic men was found to
increase their risks of head and neck SCC [OR (95 % CI) = 2.71 (1.42–5.16)] [52],
esophageal SCC [OR (95 % CI) = 3.68 (1.96–6.93)] [48], and gastric cancer [OR
(95 % CI) = 2.5 (1.2–5.2)] [41], and to increase their risk of advanced colorectal
neoplasia in an IFOBT-negative group [ORs (95 % CI) = 1.65 (1.02–2.64)] and an
IFOBT-positive group [2.83 (1.15–6.93)] [43] (Table 15.1).
276 A. Yokoyama et al.

Table 15.1 Age-adjusted odds ratios for aerodigestive neoplasia and high MCV in Japanese
alcoholic men
MCV ≥ 106 fl Controls Head and neck Controls Esophageal cancer [48]
cancer [52]
N = 215 N = 43 N = 206 N = 65
Frequency 23 % 50 % 17 % 43 %
OR (95 % CI) 1 reference 2.71 (1.42–5.16) 1 reference 3.68 (1.96–6.93)
MCV ≥ 106 fl Controls Stomach cancer [41] Controls Advanced
colorectal neoplasia [43]
N = 281 N = 45 N = 400 N = 241
Frequency 20 % 38 % 22 % 32 %
OR (95 % CI) 1 reference 2.5 (1.2–5.2) 1 reference 1.65 (1.02–2.64)a
2.83 (1.15–6.93)b
a
Immunochemical fecal occult blood test negative subjects
a
Immunochemical fecal occult blood test positive subjects

15.12 Conclusions

• The ADH1B*1/*1 genotype and ALDH2*1/*2 genotype are associated with an

increased risk of UADT neoplasia in East-Asian drinkers.
• Prolonged exposure to high ethanol and acetaldehyde concentrations and ineffi-
cient degradation of acetaldehyde in the UADT explains the high risk of UADT
neoplasia in people with these genotypes.
• Health-risk appraisal models that include alcohol flushing or ALDH2 genotype
are useful tools for mass-screening for UADT neoplasia.
• The ADH1B genotype of Japanese alcoholic men affects their body weight and
susceptibility to liver disease.
• Gastric cancer and advanced colorectal neoplasia are more common in Japanese
alcoholic men than in nonalcoholic Japanese men.
• A high MCV in Japanese alcoholic men increases their risk of aerodigestive tract
neoplasia.

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